This invention relates to products for stimulating growth of mammalian cells and methods for making and using such products. In its preferred embodiments, the invention pertains to growth factors for treating ailments of the immune system and other systems of mammals by stimulation of growth of mammalian cells, particularly T-cell lymphocytes, B-cell lymphocytes, mast cells, stem cells, fibroblasts, etc., in order to enhance or restore physiological functions provided by those cells, e.g., to enhance or restore the effectiveness of the immune system to resistance of disease.
The immune system in mammals depends substantially on the development and proliferation of T and B-cell lymphocytes for humoral and cell mediated immune response. Mammals often suffer from immuno-deficiencies, which may be congenital, such as genetically caused failures to manifest efficient humoral and/or cellular responses to infections. Some immuno deficiencies may be acquired, e.g. those associated with malnutrition, radiation, aging, malignancy or debilitation.
Most immune responses are initiated by proteins produced by a set of T lymphocytes called inducer cells. These cells synthesize and secrete peptides that stimulate growth and differentiation of many cell types, including lymphocytes and monocytes that kill foreign organisms, see Wigner et al., J. Exp. Med. 148: 1523 (1978), Yamauch et al., Eur. J. Imm. 11:905 (1981), as well as B lymphocytes, Nabel, et al. Cell 23:19, (1981), mast cells, Nabel, Nature 291: 332 (1981) and hematopoietic precursor cells, Nabel et al, Proc. Natl. Acad. Sci. U.S.A. 78:1157 (1981), the disclosure of these references being incorporated herein by reference. The biologic activities of these inducer molecules are not totally understood in molecular terms.
One approach in attempting to overcome immuno-deficiencies has been to attempt to develop products for administration which will foster rapid growth of lymphocytes in order to enhance immune response and prevent disease. See e.g. U.S. Pat. No. 4,323,561 to Nowotny, and U.S. Pat. No. 4,333,562 to Kim, the disclosures of which are incorporated herein by reference.
For example, Watson, et al., J. Exp. Med. 150:849 (1979) and others have reported the obtaining of a factor from inducer molecules which Watson called Interleucin-2 (IL-2) and which Watson, et al., also called "T-Cell Growth Factor," because of its effect on T-cell growth. See Andersoon, et al., Proc. Natl. Acad. Sci. U.S.A. 78:2497 (1981); Takatu et al., Immunol. 125:2646 (1980); McDougall et al., J. Exp. Med. 145:693 (1977), the disclosures of which are incorporated herein by reference. However, there has been a great deal of confusion and conflicting reports of properties and size of molecules IL-2 and the many other factors of lymphokines produced by different T-cells, T-cells hybridomas, etc., in response to different conditions or stimulating agents. See. Altman and D. H. Katz, "The Biology of Monoclonal Lymphokines Secreted by T Cell Lines and Hyhbridomas," Adv. Immunol. 33: 73-166 (1982), the disclosure of which is incorporated herein by reference.